Project Summary Degeneration of retinal pigment epithelium (RPE) causes vision loss in age-related macular degeneration (AMD) and retinitis pigmentosa (RP). Promoting survival of RPE (and thereby photoreceptors) is critical for preserving vision. Whereas many factors contribute to RPE degeneration in eye diseases including both genetic and environmental ones, oxidative stress is one of the major contributors to RPE dysfunction and degeneration, derived primarily from excess mitochondrial oxidative products, and phagocytosis-related lipid oxidation. However, the processes through which dysregulated oxidative stress leads to RPE dysfunction and degeneration in eye diseases remain incompletely defined. Moreover, there is lack of effective approaches to promote RPE health and survival. Identification of the basic molecular links which sense RPE redox (reduction/oxidation) environment to impact RPE dysfunction and degeneration will aid in the identification of new molecular targets to rejuvenate endogenous cellular defense system in aging RPE and prevent vision loss in eye diseases. In this project we identified a redox-sensing nuclear receptor REV-ERB?, which may act as a transcriptional regulator linking RPE redox homeostasis and RPE antioxidant defense to impact RPE degeneration. REV-ERB?, functioning as a redox- and ligand-dependent transcription factor, controls multiple biological processes including cellular metabolism, inflammation, and circadian rhythm. Our preliminary results show that: 1) REV-ERB? levels decline with aging in RPE; 2) genetic deletion of REV-ERB? in mice leads to age-related development of RPE degeneration, with subretinal deposits, impaired visual function and dampened RPE phagocytic function; 3) RPE specific deletion of REV-ERB? causes similar fundus lesions; 4) REV-ERB? deficiency exacerbates chemically-induced induced RPE damage and retinal toxicity in vivo and in vitro; 4) activation of REV-ERB? protects RPE in vitro and in vivo; and 5) REV-ERB? directly regulates nuclear factor erythroid-2 related factor 2 (NRF2) transcription and its associated antioxidant genes. We hypothesize that REV-ERB? is a novel redox-sensitive regulator of RPE intracellular antioxidant defense system, and activating REV-ERB? is a new way to protect RPE. This hypothesis will be evaluated with both genetic and pharmacological approaches of modulating REV-ERB? in both acute and chronic models of RPE damage and degeneration. Mechanistically this work will explore whether REV-ERB? protects RPE vial enhancing RPE antioxidant self-defense. This proposed work will uncover novel molecular regulatory mechanisms underlying RPE degeneration, and new druggable molecular targets for developing improved strategies to counter RPE damage and degeneration in eye diseases.